Patent DE-19959958-A1 (DE)
Title: New 2-ureido-thiazole-5-sulfonic acid amide derivatives useful as antiviral agents, especially against herpes simplex infections
Inventor: FISCHER RUEDIGER
IPC: C07D521/00
Filed: 1999-12-13
Abstract: 2-Ureido-thiazole-5-sulfonic acid amide derivatives (I) and their salts are new. 2-Ureido-thiazole-5-sulfonic acid amide derivatives of formula (I) and their salts are new. [Image] R1H, halo or 1-6C alkyl, alkoxy, aminoalkyl or haloalkyl; R2, R3H, 3-8C cycloalkyl, biphenylaminocarbonyl; or 1-6C alkyl (optionally substituted by 1-3 3-6C cycloalkyl, 1-6C alkoxy, halo, OH, 2-tetrahydrofuranyl or 5-benzo[1,3]dioxolyl; 5-6 membered heteroaryl containing 1-3 N, O and/or S, optionally bonding through N; or 3-8 membered non-aromatic heterocycle containing 1-3 N, O and/or S, optionally bonded through N and optionally substituted by OH or 1-6C alkoxy); or NR2R35-6 membered saturated heterocycle, optionally containing an O atom; R4H, 1-6C acyl or 2-6C alkenyl; or 1-6C alkyl (optionally substituted by either 1-3 halo, OH, 1-6C acyl, 1-6C alkoxy, phenoxy, 6-10C aryl or NR7R8; or by 5-6 membered heteroaryl (containing 1-3 N, O and/or S optionally bonded via N), 2-tetrahydrofuranyl, 1-R10-2-pyrrolidinyl, 2,3-dihydro-benzo[1,4]dioxin-2-yl or (R11)(R12)NC(=O)O); R7, R8H, 1-6C acyl, 1-6C alkyl, carbamoyl, mono- or di-1-6C alkylamino-1-6C alkyl, mono- or di- 1-6C alkylaminocarbonyl, 6-10C aryl or 1-6C alkoxycarbonyl; or NR7R85-6 membered heteroaryl optionally containing additional O, S or NR9heteroatoms (optionally substituted by oxo); R9H or 1-4C alkyl; R11, R12H; or 1-6C alkyl or 6-10C aryl, both optionally substituted by 1-3 OH, 1-6C alkoxy or halo; R62-oxo-3-ethyl-3H-benzoxazol-6-yl; or phenyl (optionally substituted by 1-3 halo, 6-10C aryl (itself optionally substituted by halo, NO2, NH2, OH, COOH, carbamoyl, mono- or di-1-6C alkylcarbonyl, mono- or di- 1-6C acylamino or CN; or 1-6C alkanoyl, alkoxy, alkyl, alkoxycarbonyl, haloalkyl, haloalkoxy, alkylthio, alkylsulfoxy or alkylsulfonyl), 1-6C alkoxy, 1-6C alkoxycarbonyl, 1-6 alkylthio, OH, COOH, fluorinated 1-6C alkoxy (with 1-6 F atoms), a group of formula (i)-(iii), 1-6C alkyl (optionally substituted by 2-tetrahydrofuranyl), 5-6 membered heteroaryl containing 1-3 O, N and/or S (optionally bonded through N and optionally substituted by 1-3 halo, NO2, NH2, OH, COOH, carbamoyl, mono- or di-1-6C alkylaminocarbonyl, mono- or di- 1-6C acylamino or CN; or 1-6C alkanoyl, alkoxy, alkyl, alkoxycarbonyl, haloalkoxy, alkylthio, alkylsulfoxy or alkylsulfonyl), 3-8C non-aromatic mono- or bi-cyclic heterocycle containing 1-3 O, N and/or S (optionally bonded through N and optionally substituted by 1-3 oxo, halo, OH or 1-6C alkoxycarbonyl, alkoxycarbonylamino, alkyl, haloalkyl or hydroxyalkyl) or OR14, NR15R16 or CONR17R18); R14phenyl (optionally substituted by NR19R20), 1-6C alkyl (optionally substituted by 1-3 OH) or an isoquinolin derivative of formula (iv); R15, R16H, carbamoyl, mono- or di- 1-6C alkylaminocarbonyl, phenyl or 1-6C acyl; or 1-6C alkyl (optionally substituted by 1-6C alkoxy, 1-6C acyl; or phenyl or 5-6 membered heteroaryl with 1-3 O, N and/or S heteroatoms (themselves optionally substituted by 1-3 halo and/or OH); R5, R10, R13, R17, R18H or 1-6C alkyl;; R19, R20H, 1-6C alkyl or 1-6C acyl. [Image] [Image] Independent claims are included for: (1) intermediates of formula (II); (2) preparation of (I); and (3) use of 2-[(aminocarbonyl)amino]-1,3-thiazol-5-sulfonamide derivatives (A) for preparation of medicaments [Image] A : halo. ACTIVITY : Virucide. 2-{[2-(Dimethylamino)ethyl][4-(ethoxyanilino)carbonyl]amino}-N,4-dimethyl-1,3-thiazol-5-sulfonamide (Ia) had IC50 values of 0.2 MicroM for herpes simplex virus (HSV) 1F and 1 MicroM for HSV-2G. A similar compound, 2-(3-biphenyl-4-yl-1-methyl-ureido)-4-methyl-thiazole-5-sulfonic acid methylamide had corresponding IC50 values of 1 nM and 5 nM respectively. Zovirax had IC50 values of 1 MicroM and 3 MicroM respectively. MECHANISM OF ACTION : None given.